Functional recovery after tendon injury is often limited by a biological dilemma: regenerative responses that support tissue repair may also drive maladaptive differentiation, including ectopic chondrogenesis. Piezo1, a mechanosensitive ion channel, has been increasingly implicated in tendon mechanobiology, yet its role in balancing beneficial repair and pathological remodeling remains unclear. This study aimed to define the bidirectional role of Piezo1 during tendon healing and to evaluate a localized intervention strategy using an injectable hydrogel co-delivering the Piezo1 agonist Yoda1 and the BMP pathway inhibitor LDN-193189 to enhance repair while restraining ectopic chondrogenesis.

An acute Achilles tendon injury model was established in C57BL/6J mice by partial tenotomy. Piezo1 expression was examined dynamically from day 1 to week 4 after injury. Single-cell RNA sequencing was performed on injured tendon tissue at 2 and 4 weeks to identify Piezo1-enriched cell populations and changes in cell-cell communication during healing. In vivo gain- and loss-of-function experiments were used to validate the biological effects of Piezo1 modulation. To achieve local and sustained intervention, an aldehyde-functionalized F127/carboxymethyl chitosan injectable hydrogel was prepared as a drug delivery platform. The hydrogel was characterized by morphology, rheological behavior, release profile, and cytocompatibility. Mice were randomly assigned to five groups: injury control, blank hydrogel, Yoda1-loaded hydrogel, LDN-193189-loaded hydrogel, and dual-drug-loaded hydrogel. Functional recovery was assessed using CatWalk gait analysis and hindlimb grip strength. Tissue repair and pathological chondrogenesis were evaluated by histology, Bonar scoring, quantitative PCR, and immunofluorescence. Primary tendon cells exposed to IL-1β were used for in vitro validation.

An acute Achilles tendon injury model was established in C57BL/6J mice by partial tenotomy. Piezo1 expression was examined dynamically from day 1 to week 4 after injury. Single-cell RNA sequencing was performed on injured tendon tissue at 2 and 4 weeks to identify Piezo1-enriched cell populations and changes in cell-cell communication during healing. In vivo gain- and loss-of-function experiments were used to validate the biological effects of Piezo1 modulation. To achieve local and sustained intervention, an aldehyde-functionalized F127/carboxymethyl chitosan injectable hydrogel was prepared as a drug delivery platform. The hydrogel was characterized by morphology, rheological behavior, release profile, and cytocompatibility. Mice were randomly assigned to five groups: injury control, blank hydrogel, Yoda1-loaded hydrogel, LDN-193189-loaded hydrogel, and dual-drug-loaded hydrogel. Functional recovery was assessed using CatWalk gait analysis and hindlimb grip strength. Tissue repair and pathological chondrogenesis were evaluated by histology, Bonar scoring, quantitative PCR, and immunofluorescence. Primary tendon cells exposed to IL-1β were used for in vitro validation.

An acute Achilles tendon injury model was established in C57BL/6J mice by partial tenotomy. Piezo1 expression was examined dynamically from day 1 to week 4 after injury. Single-cell RNA sequencing was performed on injured tendon tissue at 2 and 4 weeks to identify Piezo1-enriched cell populations and changes in cell-cell communication during healing. In vivo gain- and loss-of-function experiments were used to validate the biological effects of Piezo1 modulation. To achieve local and sustained intervention, an aldehyde-functionalized F127/carboxymethyl chitosan injectable hydrogel was prepared as a drug delivery platform. The hydrogel was characterized by morphology, rheological behavior, release profile, and cytocompatibility. Mice were randomly assigned to five groups: injury control, blank hydrogel, Yoda1-loaded hydrogel, LDN-193189-loaded hydrogel, and dual-drug-loaded hydrogel. Functional recovery was assessed using CatWalk gait analysis and hindlimb grip strength. Tissue repair and pathological chondrogenesis were evaluated by histology, Bonar scoring, quantitative PCR, and immunofluorescence. Primary tendon cells exposed to IL-1β were used for in vitro validation.